Regulatory Approval of Cancer Risk-Reducing (Chemopreventive) Drugs: Moving What We Have Learned into the Clinic

Meyskens, Frank L.; Curt, Gregory A.; Brenner, Dean E.; Gordon, Gary; Herberman, Ronald B.; Finn, Olivera J.; Kelloff, Gary J.; Khleif, Samir N.; Sigman, Caroline C.; Szabó, Éva

doi:10.1158/1940-6207.capr-09-0014

Cited by 45 publications

(37 citation statements)

References 65 publications

(55 reference statements)

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“…Many medications approved for treating infections, seizures, cancer, and others have the potential to increase risk based on laboratory and even sometimes human studies, and the favorable risk-benefit equation leads to the use of these medications (although risk-benefit considerations of cancer prevention drugs have proven to be a very complex issue; refs. 51,52). The same should be true for long-term NRT use given the large difference in carcinogen exposure between smoking and NRT.…”

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confidence: 97%

Long-term Nicotine Replacement Therapy: Cancer Risk in Context

Shields

2011

Cancer Prevention Research

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Nicotine replacement therapy (NRT) for up to 12 weeks is well established, safe and efficacious for fostering smoking cessation. Some smokers at a high risk of relapse may benefit from long-term use, and so long-term NRT safety and efficacy have become a paramount question for the FDA and others. Laboratory studies have indicated a carcinogenic potential of nicotine. Animal model studies reported in this issue of the journal by Maier and colleagues (beginning on page 1743) and Murphy and colleagues (beginning on page 1752), however, provide additional reassurance that NRT does not promote lung cancer. Very long-term studies of NRT effects do not yet exist and would be needed to definitively answer the question about NRT efficacy and cancer risk and some decision making will need to be made based on limited human data and experimental studies. The overall NRT safety question is complex and requires consideration of three contexts and comparator groups (long-term NRT/abstinence vs. smoking, long-term intermittent NRT/ reduced smoking vs. smoking, and long-term NRT/abstinence vs. abstinence without long-term NRT). Although the data on these issues are insufficient, the first comparison seems intuitive and may be compelling enough to allow the FDA to approve a long-term indication for NRT. An important public health goal is to help smokers and their health care providers understand the implications of potential long-term NRT risks in the context of its potential benefits and the far greater risks of continued smoking. Cancer Prev Res; 4(11); 1719-23. Ó2011 AACR.The efficacy and safety of short-term nicotine replacement therapy (NRT) for fostering long-term smoking cessation is well established, and up to 12 weeks of therapy is approved by the U.S. Food and Drug Administration (FDA; refs. 1-4). A meta-analysis indicates that there are measurable benefits in studies of 12 to 18 months of continued NRT use for relapse prevention (5), and other studies also indicate that this use is cost effective (6). An important question of considerable interest that remains today, however, is whether NRT can be recommended for long-term use, even years, to continue to promote smoking abstinence. The answer to this question requires both an efficacy and safety assessment. In this context, NRT conceptually has substantial benefits compared with long-term smoking but also, as explained later and addressed in this issue of the journal, laboratory studies suggest a potential for nicotine to foster the development of cancer.The premise of long-term NRT use is that it would prevent smoking relapse, and the risks would be limited to maintaining nicotine addiction, but without the adverse consequences of continued smoking, such as increased lung cancer risk. Like the consideration of other long-term medications, on face value it is a simple risk-benefits equation. In actuality, however, this question is not simple to answer because the risk can be considered in 3 different contexts and comparator groups namely: (i) what is the risk o...

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confidence: 97%

Long-term Nicotine Replacement Therapy: Cancer Risk in Context

Shields

2011

Cancer Prevention Research

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“…Given that cancer prevention trials typically examine cancer incidence as an outcome variable rather than cancer mortality, these trials do not mechanically fit into our conceptual framework, but we expect cancer prevention technologies to generally require long trials and thus to also be under-incentivized due to the fixed patent distortion. We start with the list of all -six -FDA approved chemoprevention drugs compiled by Meyskens et al (2011). Our qualitative investigation of the history of these FDA drug approvals suggests that all six of these approvals either relied on the use of surrogate endpoints, or were approved on the basis of publicly financed clinical trials.…”

Section: Historical Case Studies Of Fda-approved Chemoprevention Drugsmentioning

confidence: 99%

“…In order to obtain data on clinical trial length, we take advantage of the fact that the NCI registry includes -where available -a Clinicaltrials.gov trial ID number. (1) In a review article on chemoprevention drugs in the journal Cancer Prevention Research, Meyskens et al (2011) compile a list of the FDA approved drugs which prevent human cancers: BCG for bladder carcinoma in situ, Diclofenac for actinic keratoses, Celecoxib for familial adenomatous polyposis (FAP)-polyps, Photofrin for Barrett's esophagus, Tamoxifen/Raloxifene for breast cancer, and vaccines (Gardasil and Cervarix) to prevent cervical cancer. As summarized in Section 5.3, our qualitative investigation of the history of these FDA drug approvals suggests that each of these six approvals was either financed by the public sector (Tamoxifen and BCG) or relied on the use of surrogate endpoints (Diclofenac, Celecoxib, Photofrin, and cervical cancer vaccines).…”

Section: B4 Description Of Nci Cancer Clinical Trial Registry Datamentioning

confidence: 99%

Do Fixed Patent Terms Distort Innovation?: Evidence from Cancer Clinical Trials

Budish

Roin²,

Williams

2013

SSRN Journal

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“…It is notable that CVD risk reduction with antihypertensive agents also has risks of substantial toxicity. Nevertheless, these proposed reasons have a sound basis and speak to a lack of effective public education about the parallels of cancer risk reduction with CVD risk reduction, and the need to remedy this lack (6).…”

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confidence: 99%

Cancer Interception

Blackburn

2011

Cancer Prevention Research

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A common perception is that cancer risk reduction is passive, such as not smoking. However, advances in the understanding of cancer biology and in cancer treatment modalities suggest that it is now timely to consider anew cancer risk reduction by active, including pharmacologic, approaches. Risk avoidance approaches are certainly important, but other approaches are important as well, as exemplified by the irony that most new lung cancers occur in former smokers, or current avoiders. Cancer interception is the active way of combating cancer and carcinogenesis at earlier and earlier stages. A great challenge is to educate people that the development of cancers, like heart disease, typically takes years and accordingly can potentially be intercepted with risk-reducing agents in the same way that advanced cancers can be treated with drugs or that cardiovascular disease can be intercepted with antihypertensive and other risk-reducing drugs. The cancer biology behind cancer interception is increasingly solid. For example, hedgehog pathway studies of mutations in the patched homolog 1 (PTCH1) gene, which constitutively activates Smoothened (SMO), led to development of an oral SMO inhibitor active in advanced basal cell carcinoma and which, in very high-risk Gorlin syndrome patients (germ line PTCH1 mutation), is nearly completely clinically effective in intercepting basal cell neoplasia. Also, the oral immunomodulator lenalidomide, first found to be active in advanced, relapsed multiple myeloma, was highly effective in intercepting the precursor stage, high-risk smoldering multiple myeloma from progressing. These are but two exciting, recent examples of the many advances in cancer research that have created an optimal time to discover and implement cancer interception. The multifaceted roles of telomere maintenance in both fueling advanced cancers and, at early stages, keeping them at bay, also highlight how the growing knowledge of cancer biology opens avenues for cancer interception. Emerging molecular techniques, including next-generation sequencing platforms, that account for a large part of the remarkable recent advances in cancer biology are now being applied to interception of premalignancy. Keeping the medical community and public at large informed about possibilities for actively intercepting cancer will be important for gaining acceptance of this increasingly powerful approach to lessening the cancer burden. Cancer Prev Res; 4(6); 787-92. Ó2011 AACR.

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Regulatory Approval of Cancer Risk-Reducing (Chemopreventive) Drugs: Moving What We Have Learned into the Clinic

Cited by 45 publications

References 65 publications

Long-term Nicotine Replacement Therapy: Cancer Risk in Context

Long-term Nicotine Replacement Therapy: Cancer Risk in Context

Do Fixed Patent Terms Distort Innovation?: Evidence from Cancer Clinical Trials

Cancer Interception

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